Nonrheumatic atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. The Stroke Prevention in Atrial Fibrillation (SPAF) I Study showed that warfarin and aspirin were both effective for stroke prevention and the SPAF II Study identified the 60% of the SPAF cohort who have adequate stroke prophylaxis by aspirin and the 40% who do not, for whom warfarin is effective. However, adjusted- dose warfarin (INR 2.0 - 4.5) is associated with excessive bleeding risk, expense and other disutility, especially in the elderly. Main Objectives for this Proposal are: 1. To assess whether a combination of low-intensity, fixed-dose warfarin (1-3 mg/day) and aspirin (325 mg/day, enteric-coated) is equally effective but is safer and better tolerated than adjusted-dose warfarin (INR 2.0 - 3.0) in AF patients predicted to have a high risk of stroke during aspirin therapy. 2. To verify an acceptably low rate of thromboembolism during aspirin therapy in the larger group of AF patients predicted to have a low risk of stroke during aspirin therapy. Design: A randomized treatment-efficacy clinical trial to be carried out at 15 clinical sites comparing warfarin (INR 2.0 - 3.0) to combination fixed- dose warfarin (1-3 mg/day) and aspirin (325 mg/day, enteric-coated) in 1,075 AF patients with a high (6.9% per year) risk of stroke on aspirin. The dose of warfarin in the combined therapy group will be initially adjusted between 1 - 3 mg/daily to prolong the INR 1.2 - 1.5 times, then fixed during subsequent follow-up. Primary events (all ischemic strokes and systemic emboli) will be detected and verified by physician investigators blinded to treatment assignment. Low-risk (1.5% per year) AF patients (n = 425) will be enrolled at the same sites and all placed on aspirin (325 mg/day, enteric-coated), with primary events verified by a blinded Events Committee. Patients will be recruited during the first 2 years and follow-up will continue for 2 additional years (mean follow- up for 3 years). Measurement of fragment 1.2 of prothrombin and platelet activation assay by flow cytometry will be carried out to assess their value as predictors of thromboembolism and their usefulness for monitoring antithrombotic therapy. Relevance: AF occurs in 1.5 million Americans, of whom one-third will suffer stroke if untreated and accounts for 70,000 strokes yearly. AF may be the most important cause of disabling in elderly women. This project will define optimal, highly effective and well-tolerated antithrombotic therapy for AF patients to prevent stroke.